Intracranial aneurysms produce devastating, life-threatening illness in nearly 30,000 Americans each year. Most commonly, aneurysms remain asymptomatic and, as a consequence, undiagnosed until they present catastrophically with a subarachnoid hemorrhage (stroke). Despite epidemiological and laboratory research the cause or causes of cerebral aneurysms remains unknown. Clinical and laboratory research indicate that discrete subgroups of aneurysm patients exist in whom aneurysms may form by different pathophysiological There are still mechanisms. Marked increases in the serum levels of gelatinase (72kD) along with evidence of deranged collagen metabolism was observed in half the aneurysm patients studied. This has lead to the hypothesis that increased proteolytic activity damages structural proteins directly interfering with the mechanical properties of the arterial wall in such a way as to promote aneurysm formation. Metalloproteinases, such as geltinase, influence vessel remodeling and have been linked to other types of focal vascular disease (i.e., aortic aneurysm, atherosclerosis and post-angiography restenosis). This background provides the rationale for the following specific aims: 1) Initiate a series of experiments using clinical and biochemical features to define homogenous subset of aneurysm patients in whom aneurysms have a high likelihood of forming for the same reason. Increased proteolytic activity coupled with decreased structural proteins are biochemical parameters that may be used for subgrouping. 2) Initiate a series of in-depth experiments defining the mechanism of aneurysm formation in this subgroup of patients. This will involve analyzing proteolytic 3) Initiate a series of experiments to determine if increased levels of circulating geltinase can cause cerebral aneurysm in experimental animals. These aims support our long-term goals of extending the understanding of cerebral aneurysm formation and developing methods for early identification and treatment of asymptomatic patients at risk for aneurysmal subarachnoid hemorrhage.